optimal management of hormone replacement in hypopituitarism
TRANSCRIPT
Dr Miguel Debono MD MRCP PhD
Consultant Physician in Endocrinology and Acute Medicine and Honorary Senior Lecturer
May 2019
Optimal Management of Hormone Replacement in Hypopituitarism
Endocrine Society Guidelines October 2016
East Midlands Pituitary Day
Agenda
• Epidemiology of Hypopituitarism
• Individual Hormonal Deficiencies –• Monitoring and Treatment
• Hormonal Treatment Interactions
Epidemiology of Hypopituitarism
• Prevalence: 45 cases per 100000
• Incidence: 4 cases per 100000
Fernandez-Rodriquez Clinical Endo 2013 Appelman-Dijkstra JCEM 2011
Hormonal deficiency
Hypopituitarism post Stereotactic Radiosurgery
Simms-Williams et al 2019 Clinical Endo 90: 114 - 121
53% 75%
22% 30%
No
rmal
tyro
thro
ph
axis
No
rmal
axis
No
rmal
go
nad
al axis
No
rmal
go
nad
al axis
No
rmal
ad
ren
al
axis
New onset hypopituitarism 20 years after treatment
Diagnosis of Hypopituitarism
• 830am cortisol/ACTH +/-
Short Synacthen test
• TSH (only at diagnostic stage)/ T4
• FSH/LH/fasting 830 am testosterone, SHBG, oestradiol
• Prolactin (deficiency related to Sheehan’s or panhypopituitarism)
• IGF1, QOL AGHDA score, GH stimulation test
Epidemiology of Secondary AI
• Affects 150 – 280 per million inhabitants
Webb et al JCEM 1999 84: 3696 -3700
N = 234 patients88 new hormonal deficiencies in 52 patients
Post Pituitary Surgery Adrenal Insufficiency
Klose et al Clinical Endo 2005 63: 499 - 505
110
39Insufficient
71Sufficient
Preop
35
35
35
4
4
4
23
32
31
Postop
46
39
40Insufficient Sufficient Insufficient Sufficient
1 month
3 months
1 year
20% recovery of AI up to 5 years later
Munro Clinical Endo 2016
Secondary AI: Increased morbidity and mortality
• Mortality is increasedo Sherlock, JCEM 2009; 94: 4216
o Zueger, JCEM 2012; 97:1938
o Hammarstrand, EJE 2017; 177: 251
• Quality of Life is pooro Hahner, JCEM 2007; 92: 3912
o Bleicken, Clinical Endocrinology 2010; 72: 297
o Ragnarsson, EJE 2014; 171: 571
o Werumeus Buning, Neuroendoc 2016; 103:771
• Cardiovascular risk is elevatedo Filipsson, JCEM 2006; 91: 3954
o Werumeus Buning, 2016; 101: 3691
• Low Bone Mineral Densityo Ragnarsson, Clinical Endocrinology 2012; 76: 246
Monitoring Adrenal Status in Secondary AI
Pofi et al JCEM 2018; 103: 3050 - 3059
SST 30 minute cortisol >350nmol/L predicts recovery in 99%Delta cortisol >100nmol/L predicts recovery in 95%Morning cortisol >200nmol/l – good probability of recovery
N = 776 patients with reversible cause
In patients with no AI- Yearly 9am cortisol + monitor for symptoms- If > 200nmol/l and asymptomatic – repeat in 1 year- If <200nmol/l – do SST
(Yo Clinical Endo 2014)
Salivary cortisone: potential tool to assess for adrenal insufficiency – NIHR RfPB
Debono et al JCEM 2016; 101: 1469 - 1477
Thrice Daily Weight-Related HC
Total dose per day Patient Weight
(kg)
Total dose per day
(mg)
1stmorning dose
(mg)
2ndmidday dose
(mg)
3rdevening dose
(mg)
50-54 10.0 5.0 2.5 2.5
55-74 15.0 7.5 5.0 2.5
75-84 17.5 10.0 5.0 2.5
85-94 20.0 10.0 7.5 2.5
95-114 22.5 12.5 7.5 2.5
115-120 25.0 15.0 7.5 2.5
Patient Weight
(kg) (mg)
1stmorning dose
(mg)
2ndmidday dose
(mg)
3rdevening dose
(mg)
50-54 10.0 5.0 2.5 2.5
55-74 15.0 7.5 5.0 2.5
75-84 17.5 10.0 5.0 2.5
85-94 20.0 10.0 7.5 2.5
95-114 22.5 12.5 7.5 2.5
115-120 25.0 15.0 7.5 2.5
Mah et al., Clin Endo 2004,61,367-375)
• Monitoring: • Clinically • 4 hour cortisol level (Aim 150 – 350nmol/l)
0
100
200
300
400
500
600
700
800
900
1000
06 10 14 18 22 02 06
Time (24 Hour Clock)
Seru
m H
yd
roco
rtis
on
e (
nM
)
10 14 18 22 02 06
Absence of early morning (before wake-up)
exposure to cortisol
10mg
5mg
2.5mg
Current Hydrocortisone Replacement Therapy -Inadequate & Non-Circadian
Mah et al Clinical Endocrinology 2004; 61:367 - 375
Challenge: gut length and transit time
New Multiparticulate Chronocort® Formulation
Solution: multiparticulates
pH trigger coat (pH 6.8) allowing dissolution in the small bowel
Microcrystalline Bead
Hydrocortisone layer
Delayed Release Coat
Diurnal Chronocort®-006 (20mg nocte; 10mg mane) n=16 subjects
20 mg 10 mg
Geometric mean (10 – 90 th percentile)
Normative Data Chronocort®
AUC (0 – 24h) (nmol/l.h) 4697 (3560 - 6075) 5610 (4390 – 7974)
Peak cortisol (nmol/l) 594 (423 – 959) 665 (477 – 871)
Time of peak 07:52 (05:54 – 09:06) 8.5h (3.2h – 12.5h)
Whitaker et al Clinical Endocrinology 2014; 80: 554 - 561
Dual-Release HC - first once daily HC
Once dailyThrice daily
Johannsson et al., JCEM 2012; 97: 473 - 481
Immediate release
Slow release
20% lower bioavailability
Low Dose Prednisolone
Williams et al JALM 2016; 01: 152 - 161
Precipitating factors for adrenal crises
• N = 364
• 8.3 crises per 100 patient years
Precipitating factor Percentage
Gastroenteritis 23%
Fever 22%
Emotional stress 16%
Surgery 16%
Strenuous physical activity 9%
Omit glucocorticoid 4.3%
Cessation of glucocorticoid by doctor
1.7%
Cessation of glucocorticoidby patient
1.9%
Hahner et al JCEM 2015; 100: 407 - 416
Sick Day Steroid Rules • Extra steroid cover during acute illness, trauma or
surgery
• Double the normal daily steroid dose when patient has a temperature > 37.5oC
• If vomits/diarrhoea should take 20mg HC
immediately after and sip electrolyte fluids
• Severe illness (temp > 40oC or repetitive vomiting / diarrhoea) ask for medical help, administer 100mg HC im and hospital assessment
• Steroid cover is needed in surgery and labour
Central Hypothyroidism
• 50% of central hypothyroidism caused by pituitary macroadenomas
• Around 60 to 65% post pituitary surgery and after radiotherapy for brain tumours
• Low free T4 with a low, normal or slightly high TSH
• Aim T4 at upper half of range; dose 1.6 µg/kg/day
• Measure T4 before the morning dose
BM
IH
DL
TSH suff T4<13.1 T4 13 - 17 T4 >17
Low T4- High BMI- Low HDL- High TC- High TG- High WC
N=46N=54
N=54
Hypothyroidism and Cardiovascular Risk
N=54
Klose et al JCEM 2013; 98:3802 - 3810
High T4 levels- Increased vertebral fractures- Increased all-cause mortality- Increased CV events
pmol/l
Adult Growth Hormone Deficiency
• Annual incidence of 12 – 19 per million
• Assess for GH deficiency in those with high pretest probability
• Improvement in SMR on GH treatment especially in men
Pappachan et al JCEM 2015 100: 1405 - 1411
- 6 studies- 99, 000 person years follow up
GH Treatment
• Start at 0.2 – 0.4mg/day in <60y; 0.1 – 0.2mg/day in >60y
• Aim IGF1 to be slightly under the upper end of normal
• Monitor CV risk factors and QOL
• Side effects: arthralgia, myalgia, paresthesias, CTS, sleep apnoea, diabetes
Growth Hormone and Tumours
No relationship between GH treatment and cancer risk or pituitary tumour recurrence
Child et al EJE 2015 172: 779 - 790
SIRN= 8418 (treated) vs 1218Follow up 4.8 years
Growth Hormone and CV Risk Factors
Bo
dy F
at
WH
RN=43
Decrease- hsCRP- tPA- TC- VAT
Increase- HDL
Beauregard et al JCEM 2008 93: 2063 - 2071
Central Hypogonadism
• Effects 95% of patients with sellartumours and post surgery and RT
• Some related to hyperprolactinaemia
o Increase in body weight
o Decrease in lean body mass
o Abnormal lipid profile with increasing LDL and triglycerides
o Reduction in insulin sensitivity
(Levine et al Circulation 2010)
Cardiovascular Mortality and Hypogonadismin Females
N=1091 patientsN= 2383 controls
Su
rviv
al %
Age, years
Rivera et al 2009 Menopause 16: 15 - 23
HR: 0.65 HR: 1.84
Cardiovascular Mortality and Hypogonadism in Males
UntreatedN=218
TreatedN=449
Intact HPA axis
N=253
Sta
nd
ard
ise
d M
ort
ali
ty R
ati
o
Tomlinson et al Lancet 2001; 357: 425 - 431
Treatment of Hypogonadism - MenDose Monitoring
Nebido im injections(Testosterone undecanoate)
1g every 12 weeks
Trough levels
Testosterone gels(Tostran 2% or Testogel16.2mg/g)
30 – 80mg / day 4 hour levels
Restandol po capsules(TestosteroneUndecanoate)
40 – 120mg / day(twice daily)
Pre morning dose
Gonadotrophin sc injections HCG 2000Units three times / week
48 hours afterinjection
Monitoring: - Testosterone replacement: PSA and FBC at 6 weeks, 3 months, 12 months, yearly- Spermatogenesis: Testis size, sperm count and inhibin B
Treatment of Hypogonadism - FemalesFormulation Dose
Oral Oestradiol 1mg or 2mg Oestrogen only
Oral Oestradiol 1mg or 2mg with 1mg norethisterone or 10mg dydrogesterone
Sequential combined
Oral oestradiol 2mg with 1mg norethisterone or 1mg with 5mg dydrogesterone
Continuous combined
Transdermal oestradiol
0.06%gel – 2 measures Add other progesterone
Patches- 25 to 100µg twice weekly- 50micrograms with progesterone twice weekly
-oestrogen only
- Sequential or continuous combined
HRT Benefits and Risks To Remember –NICE Guidelines June 2018
• Risk for thromboembolism with transdermal formulations is similar to normal population
• When started under age 60 years are not at CV disease risk – CV risk factors should be treated
• Oral oestrogen has some risk for stroke
• HRT with oestrogen/progesterone increases risk slightly for breast cancer
• Risk for breast cancer will vary as per risk factors
Diabetes Insipidus
• Prevalence is of 7 – 10 per 100000 subjects
• Occurs in 10 to 30% of patients undergoing surgery and persists in only 2% to 7%
• Rare in non-operated pituitary adenoma
• Main causes:
o Usually craniopharyngioma or germ cell tumour
o Head trauma
o Infiltrative and inflammatory conditions
Treatment of Diabetes Insipidus
• In acute phase post-operatively use subcutaneous vasopressin on prn basis
• Decisions based on fluid input and output and biochemistry – serum osmolality/Na; urine osmolality/Na
Hormonal Interactions
• GH suppresses conversion of cortisone to cortisol therefore beware use of GH mainly in patients on cortisone
• GH reduces T4 levels and levothyroxine dose might need increasing; never assess for GH deficiency when hypothyroid
• Thyroxine enhances metabolism of glucocorticoids therefore treat AI before commencing levothyroxine
• Oestrogen raises cortisol binding globulin and thyroid binding globulins and reduces IGF1
• Glucocorticoids enhance free water secretion so AI might “hide” diabetes insipidus
Conclusion
• Morbidity and mortality is increased in hypopituitarism but hormonal replacement and careful management may increase longevity and improve QOL
• Well defined management pathways for long term follow ups are still not established
• Novel medications are in development to enable better physiological replacement and to improve compliance